The Experts below are selected from a list of 27645 Experts worldwide ranked by ideXlab platform
Shigekazu Nagata - One of the best experts on this subject based on the ideXlab platform.
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Essential roles of the Fas-Fas Ligand pathway in the development of pulmonary fibrosis
Journal of Clinical Investigation, 1999Co-Authors: Kazuyoshi Kuwano, Takehiro Yatomi, Ritsuko Kunitake, Naoki Hagimoto, Takashige Maeyama, Norio Nakamura, Masayuki Kawasaki, Shigekazu Nagata, Takashi Suda, Hiroyuki MiyazakiAbstract:The Fas Ligand is predominantly expressed in activated T lymphocytes and is one of the major effector molecules of cytotoxic T lymphocytes and natural killer cells. Previously, we found excessive apoptosis of epithelial cells and infiltrating lymphocytes expressing Fas Ligand mRNA in the lung tissue of bleomycin-induced pulmonary fibrosis in mice. Here we demonstrated that the administration of a soluble form of Fas antigen or anti-Fas Ligand antibody prevented the development of this model and that lpr and gld mice were resistant against the induction of pneumopathy. These results suggest that the Fas-Fas Ligand pathway plays an essential role in the development of pulmonary fibrosis and that preventing this pathway could have therapeutic value in lung injury and fibrosis.
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caspase 1 independent il 1β release and inflammation induced by the apoptosis inducer Fas Ligand
Nature Medicine, 1998Co-Authors: Keiko Miwa, Reiko Horai, Masahide Asano, Yoichiro Iwakura, Shigekazu Nagata, Takashi SudaAbstract:Fas Ligand is a well-characterized apoptosis inducer. Here we demonstrate that Fas Ligand induces the processing and secretion of interleukin-1β (IL-1β) in peritoneal exudate cells. This IL-1β secretion is independent of IL-1β converting enzyme (caspase 1), yet it is inhibited by caspase inhibitors, indicating that a caspase(s) in addition to IL-1β converting enzyme can process IL-1β. Inoculation of tumor cells expressing Fas Ligand into wild-type mice induces a massive neutrophil infiltration that is, in contrast, suppressed in IL-1α/β knockout mice. These results demonstrate a newly discovered role for Fas Ligand in inflammation, and challenge the dogma that apoptosis does not induce inflammation.
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downregulation of Fas Ligand by shedding
Nature Medicine, 1998Co-Authors: Shigekazu Nagata, Masato Tanaka, Toshimitsu Itai, Masashi AdachiAbstract:Apoptosis-inducing Fas Ligand (FasL) is a type II membrane protein, predominantly expressed in the activated T cells. FasL is cleaved by a putative metalloproteinase to produce a soluble form. Here, we blocked the shedding of human FasL by deleting its cleavage site. Although human Jurkat cells and mouse primary hepatocytes that express a low level of Fas were resistant to the soluble form of FasL, they were efficiently killed by membrane-bound FasL. Furthermore, soluble FasL inhibited cytotoxicity of the membrane-bound FasL. These results indicate that the membrane-bound form of FasL is the functional form and suggest that shedding of FasL is to prevent the killing of the healthy bystander cells by cytotoxic T cells.
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Caspase 1-independent IL-1β release and inflammation induced by the apoptosis inducer Fas Ligand
Nature medicine, 1998Co-Authors: Keiko Miwa, Reiko Horai, Masahide Asano, Yoichiro Iwakura, Shigekazu Nagata, Takashi SudaAbstract:Fas Ligand is a well-characterized apoptosis inducer. Here we demonstrate that Fas Ligand induces the processing and secretion of interleukin-1beta (IL-1beta) in peritoneal exudate cells. This IL-1beta secretion is independent of IL-1beta converting enzyme (caspase 1), yet it is inhibited by caspase inhibitors, indicating that a caspase(s) in addition to IL-1beta converting enzyme can process IL-1beta. Inoculation of tumor cells expressing Fas Ligand into wild-type mice induces a massive neutrophil infiltration that is, in contrast, suppressed in IL-1alpha/beta knockout mice. These results demonstrate a newly discovered role for Fas Ligand in inflammation, and challenge the dogma that apoptosis does not induce inflammation.
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Fas and Fas Ligand lpr and gld mutations
Immunology Today, 1995Co-Authors: Shigekazu Nagata, Takashi SudaAbstract:Fas Ligand (FasL) is a death factor that binds to its receptor, Fas, and induces apoptosis. Two mutations that accelerate autoimmune disease, lpr and gld, are known to correspond to mutations within genes encoding Fas and FasL, respectively. Here, Shigekazu Nagata and Takashi Suda summarize current knowledge of Fas and FasL, and discuss the physiological role of the Fas system in T-cell development, cytotoxicity and cytotoxic T lymphocyte (CTL)-mediated autoimmune disease.
Hideo Yagita - One of the best experts on this subject based on the ideXlab platform.
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Blockade of the Fas/Fas Ligand interaction suppresses hepatocyte apoptosis in ischemia-reperfusion rat liver
Apoptosis : an international journal on programmed cell death, 2008Co-Authors: Hiroo Nakajima, Hideo Yagita, Naruhiko Mizuta, Ikuya Fujiwara, Koichi Sakaguchi, Hiromitsu Ogata, Junji Magae, Takehiko KojiAbstract:Hepatic ischemia-reperfusion injury remains a significant problem for liver surgery, including transplantation, and apoptosis has been implicated in this type of hepatic injury. Here we found that through the Fas/Fas Ligand interaction apoptosis is involved in the late phase of hepatic ischemia-reperfusion injury. The appearance of apoptotic hepatocytes increases significantly after reperfusion, reaching a maximum 12 h after reperfusion. The transcription levels of Fas and Fas Ligand are increased after reperfusion. Fas is expressed on hepatocytes, while Fas Ligand is expressed on infiltrating immune cells. A close spatial and temporal association of Fas expression and apoptotic cells is demonstrated in the histological observation. These results suggest that infiltrating cells induce apoptosis of hepatocytes through the Fas/Fas Ligand interaction, leading to hepatocyte injury. Furthermore, an injection of anti-Fas antibody or neutralizing anti-Fas Ligand antibody results in a dramatic decrease in the occurrence of hepatocyte apoptosis and hepatic infiltration of macrophages and natural killer cells as well as liver injury. Our results suggest that blockage of the Fas/Fas Ligand interaction is a promising strategy for suppression of hepatic ischemia-reperfusion injury.
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Selective Upregulation of Fibroblast Fas Ligand Expression, and Prolongation of Fas/Fas Ligand-Mediated Skin Allograft Survival, by Retinoic Acid: the Skin as a Retinoide-Inducible Immune Privilege Site
The Journal of investigative dermatology, 2000Co-Authors: Atsushi Saitoh, Takeshi Kawanabe, He Weidong, Tatsuyoshi Kawamura, Shinji Shimada, Nobuhiko Kayagaki, Hideo Yagita, Ko OkumuraAbstract:Fas/Fas Ligand-mediated lymphocyte apoptosis has been implicated in the suppression of immune responses and may cause immune privilege. Human corneas exhibit immune privilege and can be transplanted across allogeneic barriers without immunosuppressive therapy, perhaps, because corneal keratinocytes express Fas Ligand. To characterize Fas and Fas Ligand expression in skin, we examined expression by murine keratinocytes, dermal fibroblasts, melanocytes, and human umbilical endothelial cells. We also studied the regulation of Fas and Fas Ligand in skin cells by retinoic acid, vitamin D3, and dexamethasone as well as various cytokines. Among the molecules and cells tested, retinoic acid selectively upregulated the expression of Fas Ligand molecule by fibroblasts. Retinoic acid-induced Fas Ligand+ fibroblasts killed Fas+ target cells, and this killing was blocked by anti-Fas Ligand antibody. The function of Fas Ligand on dermal fibroblasts in vivo was tested in a cutaneous allograft system. Histoincompatible BALB/C mouse (H-2d) donor skin was grafted on to allogeneic C57BL/6 mice (H-2b). Daily local injection of retinoic acid blocked inflammation and extended graft survival for more than 10 d. Injection of retinoic acid into Fas Ligand mutated gld/gld donor skin did not prevent leukocyte infiltration into the allograft or prolong graft survival. These experiments indicate that, in skin, retinoic acid selectively increases Fas Ligand expression by fibroblasts and that retinoic acid has potent Fas/Fas Ligand-dependent immunosuppressive activity.
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Contribution of Fas Ligand to T cell-mediated hepatic injury in mice
Gastroenterology, 1997Co-Authors: Ken-ichiro Seino, Nobuhiko Kayagaki, Kazuyoshi Takeda, K. Fukao, Kyoko Okumura, Hideo YagitaAbstract:Abstract BACKGROUND & AIMS: Fas has been implicated in liver damage. The aim of this study was to investigate the role of its Ligand to induce hepatocyte death and liver damage in T cell-dependent hepatitis. METHODS: Fas Ligand-mediated lysis of primary hepatocytes from C57BL/6 wild-type, Fas Ligand-deficient gld, and Fas-deficient lpr mice and concanavalin A-induced hepatitis in these mice were assessed. RESULTS: Freshly isolated hepatocytes from wild-type or gld mice, but not those from lpr mice, were susceptible to Fas Ligand-mediated lysis. When concanavalin A was intravenously administered into wild-type mice, they developed acute hepatic injury with massive degenerative changes in hepatocytes. In contrast, both gld and lpr mice had lower aminotransferase levels with milder histological changes. Reverse- transcription polymerase chain reaction and flow cytometric analysis showed that Fas Ligand was induced in the liver shortly after the concanavalin A injection and was predominantly expressed on intrahepatic T cells. Administration of monoclonal antibody neutralizing mouse Fas Ligand could reduce the aminotransferase increase. CONCLUSIONS: The results indicate that Fas Ligand plays a role in the T cell-dependent hepatitis induced by concanavalin A administration. (Gastroenterology 1997 Oct;113(4):1315-22)
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Herpes simplex virus type 2 inhibition of Fas Ligand expression.
Journal of virology, 1996Co-Authors: Scott F. Sieg, Dawn Smith, Zafer Yildirim, Nobuhiko Kayagaki, Hideo Yagita, Yung Huang, David L. KaplanAbstract:Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are common human pathogens. In this report we demonstrate the capacity of HSV-2, but not HSV-1, to inhibit the activity and cell surface expression of Fas Ligand, an important molecule involved in T-cell apoptosis and cell-mediated cytotoxicity. Cells infected with HSV-2 retained Fas Ligand intracellularly instead of expressing it on the cell surface. Addition of anti-Fas antibodies markedly inhibited HSV-2 viral production, suggesting that the capacity of the virus to regulate Fas Ligand expression, and thereby programmed cell death, may represent a powerful mechanism for the virus to enhance viral replication.
Aydin Arici - One of the best experts on this subject based on the ideXlab platform.
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Elevated soluble Fas Ligand levels may suggest a role for apoptosis in women with endometriosis.
Fertility and sterility, 2002Co-Authors: Juan A. Garcia-velasco, Naciye Mulayim, Umit A. Kayisli, Aydin AriciAbstract:Abstract Objective: To evaluate soluble Fas Ligand concentrations in serum and peritoneal fluid from women with endometriosis and from fertile controls without endometriosis, and to study levels of soluble Fas Ligand in conditioned media of cultured endometrial stromal cells. Design: Prospective, experimental trial. Setting: Two academic IVF centers. Patient(s): Twenty-nine fertile women without endometriosis and 57 infertile women with endometriosis (32 with stage I or II disease and 25 with stage III or IV disease). Main Outcome Measure(s): Enzyme-linked immunosorbent assay was used to measure soluble Fas Ligand concentrations in paired samples of serum and peritoneal fluid from women with and without endometriosis. Concentrations were also measured in conditioned media of cultured endometrial stromal cells at basal conditions and after stimulation with interleukin-8 (0.001–10 ng/mL) and tumor necrosis factor-α (1–10 ng/mL). Result(s): Compared with fertile controls and women with early-stage of endometriosis, women with moderate to severe endometriosis had elevated serum (87.2 ± 6.4, 88.2 ± 6.9, and 162.3 ± 7.8 pg/mL, respectively) and peritoneal fluid (81.0 ± 6.0, 80.5 ± 6.8, and 166.2 ± 10.3 pg/mL, respectively) concentrations of soluble Fas Ligand. Serum levels of soluble Fas Ligand positively correlated with levels in peritoneal fluid. Comparison of patients in the same menstrual cycle in each group revealed that increased levels of soluble Fas Ligand in patients with advanced endometriosis were not attributable to the difference in cycle phases. Soluble Fas Ligand was not detected in conditioned media of endometrial stromal cells under baseline conditions or after stimulation. Conclusion(s): Serum and peritoneal fluid of women with moderate to severe endometriosis contain elevated concentrations of soluble Fas Ligand compared to women with minimal or mild endometriosis and women without endometriosis. These findings suggest a role for apoptotic dysregulation in the pathophysiology of endometriosis.
Ko Okumura - One of the best experts on this subject based on the ideXlab platform.
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Selective Upregulation of Fibroblast Fas Ligand Expression, and Prolongation of Fas/Fas Ligand-Mediated Skin Allograft Survival, by Retinoic Acid: the Skin as a Retinoide-Inducible Immune Privilege Site
The Journal of investigative dermatology, 2000Co-Authors: Atsushi Saitoh, Takeshi Kawanabe, He Weidong, Tatsuyoshi Kawamura, Shinji Shimada, Nobuhiko Kayagaki, Hideo Yagita, Ko OkumuraAbstract:Fas/Fas Ligand-mediated lymphocyte apoptosis has been implicated in the suppression of immune responses and may cause immune privilege. Human corneas exhibit immune privilege and can be transplanted across allogeneic barriers without immunosuppressive therapy, perhaps, because corneal keratinocytes express Fas Ligand. To characterize Fas and Fas Ligand expression in skin, we examined expression by murine keratinocytes, dermal fibroblasts, melanocytes, and human umbilical endothelial cells. We also studied the regulation of Fas and Fas Ligand in skin cells by retinoic acid, vitamin D3, and dexamethasone as well as various cytokines. Among the molecules and cells tested, retinoic acid selectively upregulated the expression of Fas Ligand molecule by fibroblasts. Retinoic acid-induced Fas Ligand+ fibroblasts killed Fas+ target cells, and this killing was blocked by anti-Fas Ligand antibody. The function of Fas Ligand on dermal fibroblasts in vivo was tested in a cutaneous allograft system. Histoincompatible BALB/C mouse (H-2d) donor skin was grafted on to allogeneic C57BL/6 mice (H-2b). Daily local injection of retinoic acid blocked inflammation and extended graft survival for more than 10 d. Injection of retinoic acid into Fas Ligand mutated gld/gld donor skin did not prevent leukocyte infiltration into the allograft or prolong graft survival. These experiments indicate that, in skin, retinoic acid selectively increases Fas Ligand expression by fibroblasts and that retinoic acid has potent Fas/Fas Ligand-dependent immunosuppressive activity.
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Glandular and extraglandular expression of the Fas-Fas Ligand and apoptosis in patients with Sjögren's syndrome
Clinical and experimental rheumatology, 1998Co-Authors: Ryutaro Matsumura, K Umemiya, Kagami M, Hisao Tomioka, Tanabe E, Takao Sugiyama, Sueishi M, Atsuo Nakajima, Azuma M, Ko OkumuraAbstract:Objective To evaluate the role of Fas-Fas Ligand system-mediated apoptosis in the sialoadenitis and interstitial nephritis of Sjogren's syndrome. Methods The expression of Fas antigen and Fas Ligand in sialoadenitis and interstitial nephritis was examined by immunoperoxidase staining and the reverse transcriptase-polymeras reaction (RT-PCR) in patients with Sjogren's syndrome and in normal subjects. The appearance of DNA strand breaks during apoptosis was detected in the tissue by DNA nick end labeling methods. Results In patients with severe sialoadenitis, Fas antigen was strongly expressed on the ductal epithelial cells. In contrast, Fas antigen was not seen in the minor salivary glands of normal subjects nor in patients with mild sialoadenitis. In patients with massive mononuclear cell infiltration, some of the infiltrating cells showed the Fas Ligand. In patients with interstitial nephritis associated with Sjogren's syndrome, Fas was expressed on the tubular epithelial cells, while such expression was not observed in control subjects without interstitial nephritis. In the patients with interstitial nephritis, some of the infiltrating cells showed the Fas Ligand. Apoptotic changes were observed in the ductal epithelial cells, tubular epithelial cells and some infiltrating cells by DNA nick end labeling methods, mRNA for the Fas antigen and Fas Ligand was found to be expressed in the labial salivary glands from all SS patients by RT-PCR. Conclusion The findings of this study suggest that the Fas-Fas Ligand system may play a role in the pathogenesis of the sialoadenitis and interstitial nephritis of Sjogren's syndrome.
David L. Kaplan - One of the best experts on this subject based on the ideXlab platform.
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DIFFERENTIAL ACTIVITY OF SOLUBLE VERSUS CELLULAR Fas Ligand : REGULATION BY AN ACCESSORY MOLECULE
Cellular immunology, 1999Co-Authors: Scott F. Sieg, Dawn Smith, David L. KaplanAbstract:Fas Ligand induces apoptosis by binding to its receptor Fas. This process has been shown to be important for activation-induced cell death of T lymphocytes, homeostasis of T cell numbers, cytotoxicity, and the maintenance of immunological privilege. Fas Ligand is a type II membrane protein that is cleaved by a metalloproteinase to produce an active, soluble molecule. It has been found that a variety of target cells are differentially sensitive to soluble and membrane-associated forms of Fas Ligand. However, the explanation for this differential activity has not been determined. One proposed explanation for this differential activity is that membrane-associated Fas Ligand is more efficiently aggregated than soluble Fas Ligand. Another possibility that we have investigated is that accessory molecules may act to enhance the activity of cellular Fas Ligand. We have transfected cells to express membrane-associated Fas Ligand and have characterized clones of these transfected cells in terms of Fas Ligand and ICAM-1 surface expression. Enhanced activity was associated with enhanced levels of both Fas Ligand and ICAM-1. Moreover, inhibition of ICAM-1 modulated the activity of membrane-associated Fas Ligand so that its cellular specificity was similar to that of soluble Fas Ligand. Thus, ICAM-1 plays a significant role in regulating Fas Ligand activity, and this role explains, at least in part, the different functional attributes of the soluble versus the cell-associated molecule.
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Technical Note: Aberrant Detection of Cell Surface Fas Ligand with Anti-Peptide Antibodies
Journal of immunology (Baltimore Md. : 1950), 1998Co-Authors: Dawn Smith, Scott F. Sieg, David L. KaplanAbstract:Polyclonal rabbit Abs raised against peptides from the C-terminal region (the extracellular domain) of human Fas Ligand were produced for the detection of the molecule in Western blot analysis and immunohistochemistry. These Abs have been used by several groups of investigators to assess cell surface Fas Ligand via flow cytometry, but we show that these polyclonal rabbit Abs do not detect cell surface Fas Ligand by that technique.
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Fas Ligand deficiency in HIV disease
Proceedings of the National Academy of Sciences of the United States of America, 1997Co-Authors: Scott F. Sieg, Dawn Smith, Zafer Yildirim, David L. KaplanAbstract:Apoptosis is postulated to be involved as an anti-viral immune mechanism by killing infected cells before viral replication has occurred. The Fas–Fas Ligand interaction is a powerful regulator of T cell apoptosis and could potentially act as a potent anti-viral immune mechanism against T cell tropic virus such as human immunodeficiency virus (HIV). We investigated the status of Fas Ligand in peripheral blood mononuclear cells (PBMCs) obtained from persons infected with HIV. We found that monocytes in freshly isolated PBMCs from healthy individuals possess cell surface Fas Ligand. In contrast, monocytes in freshly isolated PBMCs from HIV-infected patients had no detectable Fas Ligand on the cell surface. Consistent with these findings of surface expression, Fas Ligand activity was deficient in the cells from HIV-infected persons. The effect of replacing Fas Ligand activity on HIV production by patients’ cells was assessed in an in vitro assay. The addition of a functional anti-Fas antibody to PBMCs from HIV-infected individuals inhibited viral production by greater than 90% without affecting lymphocytic function. These findings suggest the possibility of a new therapeutic modality for the treatment of HIV-infected individuals based on the reconstitution of Fas Ligand activity.
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Herpes simplex virus type 2 inhibition of Fas Ligand expression.
Journal of virology, 1996Co-Authors: Scott F. Sieg, Dawn Smith, Zafer Yildirim, Nobuhiko Kayagaki, Hideo Yagita, Yung Huang, David L. KaplanAbstract:Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are common human pathogens. In this report we demonstrate the capacity of HSV-2, but not HSV-1, to inhibit the activity and cell surface expression of Fas Ligand, an important molecule involved in T-cell apoptosis and cell-mediated cytotoxicity. Cells infected with HSV-2 retained Fas Ligand intracellularly instead of expressing it on the cell surface. Addition of anti-Fas antibodies markedly inhibited HSV-2 viral production, suggesting that the capacity of the virus to regulate Fas Ligand expression, and thereby programmed cell death, may represent a powerful mechanism for the virus to enhance viral replication.
